Can pharmacogenetics help patients under chronic treatment with coumarin anticoagulants?
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Isabel López
Abstract
Vitamin K antagonists are highly effective antithrombotic drugs. However, appropriate dosing is difficult to establish owing to its narrow therapeutic window as well as widespread inter- and intra-individual variability in dosage. Compared with dosing solely based on clinical information, pharmacogenetics can help improve the therapy with coumarins by decreasing the time to reach a stable dose and reducing the risk of bleeding. Most of the studies about genotyping of patients using vitamin K antagonists have focused on predicting the stable dose. Two genes have been shown to have the most influence on dosing: VKORC1 and CYP2C9. Furthermore, genotyping of more genes, such as CYP4F2 and APOE, is also being included in some dosing algorithms. The role of genotype beyond the initial dose-titration phase is less clear. Thus, a proven genetically determined risk of unstable dose or bleeding could help with the selection of patients who require more frequent monitoring of dose. On the other hand, patients who have a genetically determined stable dose could self-monitor their international normalized ratio (INR), making the therapy less expensive and more convenient.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: GreenLife Research Group (Universidad San Jorge) is funded by DGA (Spain): E105.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Teichert M, Eijgelsheim M, Rivadeneira F, Uitterlinden AG, van Schaik RH, Hofman A, et al. A genome-wide association study of acenocoumarol maintenance dosage. Hum Mol Genet 2009;18:3758–68.10.1093/hmg/ddp309Suche in Google Scholar PubMed
2. Pérez-Andreu V, Roldán V, López-Fernández MF, Antón AI, Alberca I, Corral J, et al. Pharmacogenetics of acenocoumarol in patients with extreme dose requirements. J Thromb Haemost 2010;8:1012–7.10.1111/j.1538-7836.2010.03800.xSuche in Google Scholar PubMed
3. Roskell NS, Samuel M, Noack H, Monz BU. Major bleeding in patients with atrial fibrillation receiving vitamin K antagonists: a systematic review of randomized and observational studies. Europace 2013;15:787–97.10.1093/europace/eut001Suche in Google Scholar PubMed PubMed Central
4. van Schie RM, Wessels JA, le Cessie S, de Boer A, Schalekamp T, van der Meer FJ, et al. Loading and maintenance dose algorithms for phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data. Eur Heart J 2011;32:1909–17.10.1093/eurheartj/ehr116Suche in Google Scholar PubMed
5. Nastasi-Catanese JA, Padilla-Gutiérrez JR, Valle Y, Ortega-Gutiérrez F, Gallegos-Arreola MP, Figuera LE. Genetic contribution of CYP2C9, CYP2C19, and APOE variants in acenocoumarol response. Genet Mol Res 2013;12:4413–21.10.4238/2013.October.10.7Suche in Google Scholar PubMed
6. Visser LE, Trienekens PH, De Smet PA, Vulto AG, Hofman A, van Duijn CM, et al. Patients with an ApoE epsilon4 allele require lower doses of coumarin anticoagulants. Pharmacogenet Genomics 2005;15:69–74.10.1097/01213011-200502000-00002Suche in Google Scholar PubMed
7. Wypasek E, Branicka A, Awsiuk M, Sadowski J, Undas A. Genetic determinants of acenocoumarol and warfarin maintenance dose requirements in Slavic population: a potential role of CYP4F2 and GGCX polymorphisms. Thromb Res 2014;134:604–9.10.1016/j.thromres.2014.06.022Suche in Google Scholar PubMed
8. Uno T, Sugimoto K, Sugawara K, Tateishi T. The effect of CYP2C19 genotypes on the pharmacokinetics of warfarin enantiomers. J Clin Pharm Ther 2008;33:67–73.10.1111/j.1365-2710.2008.00887.xSuche in Google Scholar PubMed
9. Arboix M, Frati ME, Laporte JR. The potentiation of acenocoumarol anticoagulant effect by amiodarone. Br J Clin Pharmacol 1984;18:355–60.10.1111/j.1365-2125.1984.tb02476.xSuche in Google Scholar PubMed PubMed Central
10. Finkelman BS, Gage BF, Johnson JA, Brensinger CM, Kimmel SE. Genetic warfarin dosing: tables versus algorithms. J Am Coll Cardiol 2011;57:612–8.10.1016/j.jacc.2010.08.643Suche in Google Scholar PubMed PubMed Central
11. Sun X, Yu WY, Ma WL, Huang LH, Yang GP. Impact of the gene polymorphisms on the warfarin maintenance dose: a systematic review and meta-analysis. Biomed Rep 2016;4:498–506.10.3892/br.2016.599Suche in Google Scholar PubMed PubMed Central
12. Caldwell MD, Awad T, Johnson JA, Gage BF, Falkowski M, Gardina P, et al. CYP4F2 genetic variant alters required warfarin dose. Blood 2008;111:4106–12.10.1182/blood-2007-11-122010Suche in Google Scholar PubMed PubMed Central
13. Borobia AM, Lubomirov R, Ramírez E, Lorenzo A, Campos A, Muñoz-Romo R, et al. An acenocoumarol dosing algorithm using clinical and pharmacogenetic data in Spanish patients with thromboembolic disease. PLoS One 2012;7:e41360.10.1371/journal.pone.0041360Suche in Google Scholar PubMed PubMed Central
14. Gong IY, Tirona RG, Schwarz UI, Crown N, Dresser GK, Larue S, et al. Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy. Blood 2011;118:3163–71.10.1182/blood-2011-03-345173Suche in Google Scholar PubMed
15. Cerezo-Manchado JJ, Rosafalco M, Antón AI, Pérez-Andreu V, Garcia-Barberá N, Martinez AB, et al. Creating a genotype-based dosing algorithm for acenocoumarol steady dose. Thromb Haemost 2013;109:146–53.10.1160/TH12-08-0631Suche in Google Scholar PubMed
16. Wolkanin-Bartnik J, Pogorzelska H, Szperl M, Bartnik A, Koziarek J, Bilinska ZT. Impact of genetic and clinical factors on dose requirements and quality of anticoagulation therapy in Polish patients receiving acenocoumarol: dosing calculation algorithm. Pharmacogenet Genomics 2013;23:611–8.10.1097/FPC.0000000000000004Suche in Google Scholar PubMed
17. Ferrari M, Romualdi E, Dentali F, Squizzato A, Marino F, Cosentino M, et al. Association between ABCG2 and ABCB1 genes and warfarin stability: a case-control study. Thromb Res 2014;134:1359–62.10.1016/j.thromres.2014.09.017Suche in Google Scholar PubMed
18. Vorob’eva NM, Panchenko EP, Dobrovol’skii AB, Titaeva EV, Khasanova ZB, Konovalova NV, et al. Polymorphisms of genes CYP2C9 and VKORC1 in patients with venous thromboembolic complications in Moscow population: effects on stability of anticoagulant therapy and frequency of hemorrhage. Ter Arkh 2011;83:59–65.Suche in Google Scholar
19. Tàssies D, Freire C, Pijoan J, Maragall S, Monteagudo J, Ordinas A, et al. Pharmacogenetics of acenocoumarol: cytochrome P450 CYP2C9 polymorphisms influence dose requirements and stability of anticoagulation. Haematologica 2002;87:1185–91.Suche in Google Scholar
20. Kimmel SE, French B, Kasner SE, Johnson JA, Anderson JL, Gage BF, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med 2013;369:2283–93.10.1056/NEJMoa1310669Suche in Google Scholar PubMed PubMed Central
21. Verhoef TI, Ragia G, de Boer A, Barallon R, Kolovou G, Kolovou V, et al. A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N Engl J Med 2013;369:2304–12.10.1056/NEJMoa1311388Suche in Google Scholar PubMed
22. Verhoef TI, Redekop WK, de Boer A, Maitland-van der Zee AH, group E-P. Economic evaluation of a pharmacogenetic dosing algorithm for coumarin anticoagulants in The Netherlands. Pharmacogenomics 2015;16:101–14.10.2217/pgs.14.149Suche in Google Scholar PubMed
23. Wadelius M, Chen LY, Eriksson N, Bumpstead S, Ghori J, Wadelius C, et al. Association of warfarin dose with genes involved in its action and metabolism. Hum Genet 2007;121:23–34.10.1007/s00439-006-0260-8Suche in Google Scholar PubMed PubMed Central
24. Bodin L, Verstuyft C, Tregouet DA, Robert A, Dubert L, Funck-Brentano C, et al. Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood 2005;106:135–40.10.1182/blood-2005-01-0341Suche in Google Scholar PubMed
25. Cadamuro J, Dieplinger B, Felder T, Kedenko I, Mueller T, Haltmayer M, et al. Genetic determinants of acenocoumarol and phenprocoumon maintenance dose requirements. Eur J Clin Pharmacol 2010;66:253–60.10.1007/s00228-009-0768-7Suche in Google Scholar PubMed
26. Cini M, Legnani C, Cosmi B, Guazzaloca G, Valdrè L, Frascaro M, et al. The influence of VKORC1 3730 G>A polymorphism on warfarin dose: reply. Eur J Clin Pharmacol 2013;69:1045.10.1007/s00228-012-1431-2Suche in Google Scholar PubMed
27. Miller GP, Lichti CF, Zielinska AK, Mazur A, Bratton SM, Gallus-Zawada A, et al. Identification of hydroxywarfarin binding site in human UDP glucuronosyltransferase 1a10: phenylalanine90 is crucial for the glucuronidation of 6- and 7-hydroxywarfarin but not 8-hydroxywarfarin. Drug Metab Dispos 2008;36:2211–8.10.1124/dmd.108.022863Suche in Google Scholar PubMed PubMed Central
28. Thijssen HH, Flinois JP, Beaune PH. Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes. Drug Metab Dispos 2000;28:1284–90.10.1016/S0090-9556(24)15074-XSuche in Google Scholar
29. Lee S, Hwang HJ, Kim JM, Chung CS, Kim JH. CYP2C19 polymorphism in Korean patients on warfarin therapy. Arch Pharm Res 2007;30:344–9.10.1007/BF02977616Suche in Google Scholar PubMed
30. Jiménez-Varo E, Cañadas-Garre M, Gutiérrez-Pimentel MJ, Calleja-Hernández MA. Prediction of stable acenocoumarol dose by a pharmacogenetic algorithm. Pharmacogenet Genomics 2014;24:501–13.10.1097/FPC.0000000000000082Suche in Google Scholar PubMed
31. Stec DE, Roman RJ, Flasch A, Rieder MJ. Functional polymorphism in human CYP4F2 decreases 20-HETE production. Physiol Genomics 2007;30:74–81.10.1152/physiolgenomics.00003.2007Suche in Google Scholar PubMed
32. Chen P, Sun YQ, Yang GP, Li R, Pan J, Zhou YS. Influence of the CYP4F2 polymorphism on the risk of hemorrhagic complications in coumarin-treated patients. Saudi Med J 2016;37:361–8.10.15537/smj.2016.4.14036Suche in Google Scholar PubMed PubMed Central
33. Scott J, Knott TJ, Shaw DJ, Brook JD. Localization of genes encoding apolipoproteins CI, CII, and E to the p13----cen region of human chromosome 19. Hum Genet 1985;71:144–6.10.1007/BF00283370Suche in Google Scholar PubMed
34. Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009;360:753–64.10.1056/NEJMoa0809329Suche in Google Scholar PubMed PubMed Central
35. Wadhera RK, Russell CE, Piazza G. Cardiology patient page. Warfarin versus novel oral anticoagulants: how to choose? Circulation 2014;130:e191–3.10.1161/CIRCULATIONAHA.114.010426Suche in Google Scholar PubMed
36. Baranova EV, Verhoef TI, Asselbergs FW, de Boer A, Maitland-van der Zee AH. Genotype-guided coumarin dosing: where are we now and where do we need to go next? Expert Opin Drug Metab Toxicol 2015;11:509–22.10.1517/17425255.2015.1004053Suche in Google Scholar PubMed
37. Hanley CM, Kowey PR. Are the novel anticoagulants better than warfarin for patients with atrial fibrillation? J Thorac Dis 2015;7:165–71.Suche in Google Scholar
38. Pink J, Pirmohamed M, Lane S, Hughes DA. Cost-effectiveness of pharmacogenetics-guided warfarin therapy vs. alternative anticoagulation in atrial fibrillation. Clin Pharmacol Ther 2014;95:199–207.10.1038/clpt.2013.190Suche in Google Scholar PubMed
39. You JH. Pharmacogenetic-guided selection of warfarin versus novel oral anticoagulants for stroke prevention in patients with atrial fibrillation: a cost-effectiveness analysis. Pharmacogenet Genomics 2014;24:6–14.10.1097/FPC.0000000000000014Suche in Google Scholar PubMed
40. Verhoef TI, Redekop WK, Veenstra DL, Thariani R, Beltman PA, van Schie RM, et al. Cost-effectiveness of pharmacogenetic-guided dosing of phenprocoumon in atrial fibrillation. Pharmacogenomics 2013;14:869–83.10.2217/pgs.13.74Suche in Google Scholar PubMed
©2016 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Editorial
- The Santorini Conferences continue
- Mini Reviews
- CYP2D6 variability in populations from Venezuela
- Can pharmacogenetics help patients under chronic treatment with coumarin anticoagulants?
- Pharmacogenetic studies: a tool to improve antidepressant therapy
- Original Articles
- 1846G>A polymorphism of CYP2D6 gene and extrapyramidal side effects during antipsychotic therapy among Russians and Tatars: a pilot study
- SLC22A2 – mapping genomic variations within South African indigenous and admixed populations
- Improvement of the chemical inhibition phenotyping assay by cross-reactivity correction
- Enhanced oral bioavailability of metoprolol with gallic acid and ellagic acid in male Wistar rats: involvement of CYP2D6 inhibition
- Case Report
- Vancomycin-induced thrombocytopenia in a newborn
- Acknowledgment
- Acknowledgment
- Congress Abstracts
- 8th Santorini Conference Systems Medicine and Personalised Health and Therapy
Artikel in diesem Heft
- Frontmatter
- Editorial
- The Santorini Conferences continue
- Mini Reviews
- CYP2D6 variability in populations from Venezuela
- Can pharmacogenetics help patients under chronic treatment with coumarin anticoagulants?
- Pharmacogenetic studies: a tool to improve antidepressant therapy
- Original Articles
- 1846G>A polymorphism of CYP2D6 gene and extrapyramidal side effects during antipsychotic therapy among Russians and Tatars: a pilot study
- SLC22A2 – mapping genomic variations within South African indigenous and admixed populations
- Improvement of the chemical inhibition phenotyping assay by cross-reactivity correction
- Enhanced oral bioavailability of metoprolol with gallic acid and ellagic acid in male Wistar rats: involvement of CYP2D6 inhibition
- Case Report
- Vancomycin-induced thrombocytopenia in a newborn
- Acknowledgment
- Acknowledgment
- Congress Abstracts
- 8th Santorini Conference Systems Medicine and Personalised Health and Therapy
